NEPHROTOXIC NEPHRITIS IN CCR5 AND CXCR3 KNOCKOUT MICE

肾小球炎症、新月体形成和间质纤维化是严重肾小球肾炎（GN）的主要特征，由白细胞浸润介导。这种渗透是由许多趋化剂的协同释放引起的。近年来，趋化因子在该病中的作用引起了人们的广泛关注。人体研究显示，肾小球和肾小球中几种趋化因子（RANTES、MIP-1 β、MCP-1）和趋化因子受体（CCR 5、CXCR 3）上调，但其功能作用在很大程度上仍未确定。类似地，在炎症性GN的动物模型中的研究已经显示了在疾病的不同阶段几种趋化因子和趋化因子受体的上调。特别是趋化因子MIP 1-β、MCP-1、RANTES、MIP-2、嗜酸性粒细胞趋化因子受体在疾病的不同阶段。特别是趋化因子MIP 1-β、MCP-1、RANTES、MIP-2、嗜酸性粒细胞趋化因子受体在疾病的不同阶段。特别是趋化因子MIP 1-β、MCP-1、RANTES、MIP-2、嗜酸性粒细胞趋化因子、IP 10和趋化因子（fractalkine）以及趋化因子受体。CCR 1、CCR 2、CCR 5和CXCR 3在新月体GN模型中高度表达。此外，趋化因子及其受体影响Th 1和Th 2辅助性T细胞亚群之间的平衡。这反过来可能会改变实验性新月体GN的严重程度，这主要是由于TH 1反应。我们假设在这个建议中，破坏CCR 5或CXCR 3将影响新月体肾炎小鼠模型中肾小球新月体和炎症后间质纤维化的发展，并改变Th 1和Th 2之间的平衡，以响应外源性抗原。我们计划在使用CCR 5或CXCR 3缺陷小鼠的小鼠肾毒性肾炎的加速模型中与使用CCR 5或CXCR 3缺陷小鼠的小鼠肾毒性肾炎的加速模型相比，与野生型对照相比，检验这一假设。研究破坏这两种趋化因子受体及其配体对野生型对照的影响。研究破坏这两种趋化因子受体及其配体对GN的发展和进展以及启动免疫反应的影响，将对设计治疗方法以中和肾小球和其他自身免疫性疾病中的这些强效炎症介质具有重要意义。

Glomerular inflammation, crescent formation and interstitial fibrosis, the major features of severe glomerulonephritis (GN), are mediated by the infiltration of leukocytes. This infiltrate results from the coordinated release of a number of chemotatic. Recently much attention has focused on the role of chemokines in this disease. Studies in humans have shown up-regulation of several chemokines (RANTES, MIP-1beta, MCP-1) and chemokine receptors (CCR5, CXCR3) in renal glomeruli and interstitium but their functional role remains largely undefined. Similarly, studies in animal models of inflammatory GN have shown up-regulation of several chemokines and chemokine receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, IP10, and lymphotactin (fractalkine), and the chemokine receptors. CCR1, CCR2, CCR5, and CXCR3 are highly expressed in models of crescentic GN. In addition, chemokines and their receptors influence the balance between the Th1 and Th2 helper T cell subsets. This in turn may alter the severity of experimental crescentic GN, which results from a predominantly TH1 response. We hypothesize in this proposal that disrupting CCR5 or CXCR3 will affect the development of glomerular crescents and post-inflammatory interstitial fibrosis in a murine model of crescentic GN and alter the balance between Th1 and Th2 in the response to exogenous antigen. We plan to test this hypothesis in an accelerated model of murine nephrotoxic nephritis using mice deficient in either CCR5 or CXCR3 as compared to an accelerated model of murine nephrotoxic nephritis using mice deficient in either CCR5 or CXCR3 as compared to wild type controls. Studying the effects of disrupting these two chemokine receptors and their ligands on the wild type controls. Studying the effects of disrupting these two chemokine receptors and their ligands on the development and progression of GN and the initiating immune response will have important implications for the design of therapies to neutralize these potent inflammatory mediators in glomerular and other autoimmune diseases.